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Indian Journal of Ophthalmology Jul 2024
Topics: Humans; Retinoblastoma; India; Retinal Neoplasms
PubMed: 38905457
DOI: 10.4103/IJO.IJO_301_24 -
European Journal of Medical Genetics Jun 2024Retinoblastoma is the most common eye cancer in children. It is caused by pathogenic alterations of both alleles of the tumor suppressor gene RB1. In heritable...
Retinoblastoma is the most common eye cancer in children. It is caused by pathogenic alterations of both alleles of the tumor suppressor gene RB1. In heritable retinoblastoma, a constitutional RB1 variant predisposes the cells to tumor formation, and loss of the other allele is a prerequisite for the development of retinoblastoma. Heritable retinoblastoma is inherited in an autosomal dominant manner; however, the majority of cases are the result of a de novo pathogenic RB1 variant. Penetrance is usually high (>90%), but with marked inter-familial variability. In some families, penetrance is incomplete and family members who develop tumors tend to remain unilaterally affected. Moreover, some families with low penetrance also show a parent-of-origin effect. We describe a patient with unilateral retinoblastoma caused by a previously unreported likely pathogenic RB1 variant (c.1199T>C) that disrupts a highly conserved amino acid residue within the A-box functional domain. Segregation analysis showed that the variant had unusually low penetrance as nine non-affected family members carried the same variant. We emphasize the use of genetic analysis on tumor DNA for classifying the RB1 variant, and underline the challenges in clinical management and counseling of families carrying the specific RB1 variant.
PubMed: 38897371
DOI: 10.1016/j.ejmg.2024.104956 -
Clinics (Sao Paulo, Brazil) 2024Patients with Human Papillomavirus (HPV+)-associated Laryngeal Squamous Cell Carcinoma (LSCC) exhibit dramatically improved survival relative to those with HPV-Negative...
INTRODUCTION
Patients with Human Papillomavirus (HPV+)-associated Laryngeal Squamous Cell Carcinoma (LSCC) exhibit dramatically improved survival relative to those with HPV-Negative (HPV-) tumors. In this study, the authors aimed to investigate the radiosensitivity of all available confirmed HPV+ and HPV-LSCC cells in vitro and in vivo.
METHODS
Primary LSCC cells were generated from tumor specimens obtained from patients. Real-time PCR was performed to confirm HPV infection and the expression of HPV-related genes (E6 and E7), p53, and pRB. Clonogenic survival assays, western blotting, and flow cytometry were used to assess radiation sensitivity, apoptosis, and the expression of p53 and pRB. p53 and pRB knockout cells were generated using CRISPR/Cas9 technology.
RESULTS
HPV+ LSCC cells displayed enhanced radiation sensitivity compared to HPV- cells. Radiation-induced apoptosis in HPV+ LSCC cells, accompanied by increased levels of p53 and pRB. Knockout of p53 or pRB led to radiation resistance and attenuated radiation-induced apoptosis in HPV+ LSCC cells. In vivo experiments showed similar results, where knockout of p53 or pRB decreased radiosensitivity in tumor-bearing mice.
CONCLUSION
The present findings demonstrated that HPV+ LSCC cells displayed obvious inherent radiation sensitivity, corresponding to increased apoptosis following radiation exposure. Mechanism study showed that the expression of p53 and pRB in HPV+ cells are required for radiation sensitivity. These findings highlight a novel mechanism by which p53 and pRB play key roles in the radiation sensitivity of HPV+ LSCC compared to HPV-LSCC.
Topics: Humans; Laryngeal Neoplasms; Carcinoma, Squamous Cell; Tumor Suppressor Protein p53; Radiation Tolerance; Papillomavirus Infections; Apoptosis; Animals; Cell Line, Tumor; Real-Time Polymerase Chain Reaction; Male; Mice; Flow Cytometry; Blotting, Western; Retinoblastoma Protein
PubMed: 38897099
DOI: 10.1016/j.clinsp.2024.100415 -
MedRxiv : the Preprint Server For... Jun 2024Outcomes for adult patients with a high-grade glioma continue to be dismal and new treatment paradigms are urgently needed. To optimize the opportunity for discovery, we...
Outcomes for adult patients with a high-grade glioma continue to be dismal and new treatment paradigms are urgently needed. To optimize the opportunity for discovery, we performed a phase 0/1 dose-escalation clinical trial that investigated tumor pharmacokinetics, pharmacodynamics, and single nucleus transcriptomics following combined ribociclib (CDK4/6 inhibitor) and everolimus (mTOR inhibitor) treatment in recurrent high-grade glioma. Patients with a recurrent high-grade glioma (n = 24) harboring 1) / deletion or / amplification, 2) loss or mutations, and 3) wild-type retinoblastoma protein (Rb) were enrolled. Patients received neoadjuvant ribociclib and everolimus treatment and no dose-limiting toxicities were observed. The median unbound ribociclib concentrations in Gadolinium non-enhancing tumor regions were 170 nM (range, 65 - 1770 nM) and 634 nM (range, 68 - 2345 nM) in patients receiving 5 days treatment at the daily dose of 400 and 600 mg, respectively. Unbound everolimus concentrations were below the limit of detection (< 0.1 nM) in both enhancing and non-enhancing tumor regions at all dose levels. We identified a significant decrease in MIB1 positive cells suggesting ribociclib-associated cell cycle inhibition. Single nuclei RNAseq (snRNA) based comparisons of 17 IDH-wild-type on-trial recurrences to 31 IDH-wild-type standard of care treated recurrences data demonstrated a significantly lower fraction of cycling and neural progenitor-like (NPC-like) malignant cell populations. We validated the CDK4/6 inhibitor-directed malignant cell state shifts using three patient-derived cell lines. The presented clinical trial highlights the value of integrating pharmacokinetics, pharmacodynamics, and single nucleus transcriptomics to assess treatment effects in phase 0/1 surgical tissues, including malignant cell state shifts. ClinicalTrials.gov identifier: NCT03834740 .
PubMed: 38883740
DOI: 10.1101/2024.06.07.24308439 -
Frontiers in Pediatrics 2024Ophthalmopathy occurring in childhood can easily lead to irreversible visual impairment, and therefore a great deal of clinical and fundamental researches have been...
BACKGROUND
Ophthalmopathy occurring in childhood can easily lead to irreversible visual impairment, and therefore a great deal of clinical and fundamental researches have been conducted in pediatric ophthalmopathy. However, a few studies have been performed to analyze such large amounts of research using bibliometric methods. This study intended to apply bibliometric methods to analyze the research hotspots and trends in pediatric ophthalmopathy, providing a basis for clinical practice and scientific research to improve children's eye health.
METHODS
Publications related to pediatric ophthalmopathy were searched and identified in the Web of Science Core Collection (WoSCC) database. Bibliometric and visualized analysis was performed using the WoSCC analysis system and CiteSpace.6.2.6 software, and high-impact publications were analyzed.
RESULTS
This study included a total of 7,177 publications from 162 countries and regions. Of these, 2,269 from the United States and 1,298 from China. The centrality and H-index were highest in the United States at 0.27 and 66, respectively. The University of London and Harvard University had the highest H-index at 37. Freedman,Sharon F published 55 publications, with the highest H-index at 19. The emerging burst keyword in 2020-2023 was "eye tracking," and the burst keywords in 2021-2023 were "choroidal thickness," "pediatric ophthalmology," "impact" and "childhood glaucoma." Retinopathy of prematurity, myopia, retinoblastoma and uveitis in juvenile idiopathic arthritis were the main topics in the high-impact publications, with clinical studies in the majority, especially in retinopathy of prematurity.
CONCLUSION
Eye health in children is a research hotspot, with the United States publishing the largest number of papers and having the greatest influence in research on pediatric ophthalmopathy, and China coming in second. The University of London and Stanford University had the greatest influence. Freedman, Sharon F was the most influential author. Furthermore, "choroidal thickness," "pediatric ophthalmology," "impact," "childhood glaucoma" and "eye tracking"are the latest hotspots in the field of pediatric ophthalmopathy. These hotspots represent hot diseases, hot technologies and holistic concepts, which are exactly the research trends in the field of pediatric ophthalmopathy, providing guidance and grounds for clinical practice and scientific research on children's eye health.
PubMed: 38873588
DOI: 10.3389/fped.2024.1405110 -
Cell Death Discovery Jun 2024A key feature of cancer is the disruption of cell cycle regulation, which is characterized by the selective and abnormal activation of cyclin-dependent kinases (CDKs)....
A key feature of cancer is the disruption of cell cycle regulation, which is characterized by the selective and abnormal activation of cyclin-dependent kinases (CDKs). Consequently, targeting CDKs via meriolins represents an attractive therapeutic approach for cancer therapy. Meriolins represent a semisynthetic compound class derived from meridianins and variolins with a known CDK inhibitory potential. Here, we analyzed the two novel derivatives meriolin 16 and meriolin 36 in comparison to other potent CDK inhibitors and could show that they displayed a high cytotoxic potential in different lymphoma and leukemia cell lines as well as in primary patient-derived lymphoma and leukemia cells. In a kinome screen, we showed that meriolin 16 and 36 prevalently inhibited most of the CDKs (such as CDK1, 2, 3, 5, 7, 8, 9, 12, 13, 16, 17, 18, 19, 20). In drug-to-target modeling studies, we predicted a common binding mode of meriolin 16 and 36 to the ATP-pocket of CDK2 and an additional flipped binding for meriolin 36. We could show that cell cycle progression and proliferation were blocked by abolishing phosphorylation of retinoblastoma protein (a major target of CDK2) at Ser612 and Thr82. Moreover, meriolin 16 prevented the CDK9-mediated phosphorylation of RNA polymerase II at Ser2 which is crucial for transcription initiation. This renders both meriolin derivatives as valuable anticancer drugs as they target three different Achilles' heels of the tumor: (1) inhibition of cell cycle progression and proliferation, (2) prevention of transcription, and (3) induction of cell death.
PubMed: 38862521
DOI: 10.1038/s41420-024-02056-6 -
Investigative Ophthalmology & Visual... Jun 2024Regression of retinoblastoma vitreous seeds (VS) during intravitreal chemotherapy can be delayed, resulting in supernumerary injections. Similarly, VS relapse may not be...
PURPOSE
Regression of retinoblastoma vitreous seeds (VS) during intravitreal chemotherapy can be delayed, resulting in supernumerary injections. Similarly, VS relapse may not be clinically evident at first. A predictive biomarker of tumor regression and relapse could help guide real-time clinical decision making. Retinoblastoma is an oxygen-sensitive tumor; paradoxically, VS survive in the hypoxic vitreous. We hypothesized that VS elaborate pro-angiogenic cytokines. The purpose was to determine if pro-angiogenic cytokine signatures from aqueous humor could serve as a biomarker of VS response to treatment.
METHODS
Multiplex ELISA was performed on aqueous from rabbit eyes with human retinoblastoma VS xenografts to identify expressed proangiogenic cytokines and changes in aqueous cytokine levels during intravitreal treatment were determined. Confirmatory RNAscope in situ hybridization for VEGF-A was performed on human retinoblastoma tumor sections and VS xenografts from rabbits. For human eyes undergoing intravitreal chemotherapy, serial aqueous VEGF-A levels measured via VEGF-A-specific ELISA were compared to clinical response.
RESULTS
VEGF-A was highly expressed in human retinoblastoma VS in the xenograft model, and was the only proangiogenic cytokine that correlated with VS disease burden. In rabbits, aqueous VEGF-A levels decreased in response to therapy, consistent with quantitative VS reduction. In patients, aqueous VEGF-A levels associated with clinical changes in disease burden (regression, stability, or relapse), with changes in VEGF-A levels correlating with clinical response.
CONCLUSIONS
Aqueous VEGF-A levels correlate with extent of retinoblastoma VS, suggesting that aqueous VEGF-A may serve as a predictive molecular biomarker of treatment response.
Topics: Retinoblastoma; Animals; Retinal Neoplasms; Vascular Endothelial Growth Factor A; Aqueous Humor; Humans; Vitreous Body; Rabbits; Biomarkers, Tumor; Enzyme-Linked Immunosorbent Assay; Liquid Biopsy; Intravitreal Injections; Neoplasm Seeding; Female; Angiogenesis Inhibitors; Cytokines
PubMed: 38861274
DOI: 10.1167/iovs.65.6.18 -
Infection Prevention in Practice Sep 2024Gastroenteritis accounts for about 10% of the deaths among children, especially in immunocompromised children. Few studies on the prevalence of gastrointestinal...
BACKGROUND
Gastroenteritis accounts for about 10% of the deaths among children, especially in immunocompromised children. Few studies on the prevalence of gastrointestinal infections caused by RNA viruses have been done in Iran. The aim of the study was to evaluate the detection of RNA viruses causing diarrhoea using a multiplex PCR.
METHODS
Stool samples were collected from 130 paediatric patients with diarrhoea who had acute lymphocytic leukaemia, non-Hodgkin lymphoma, and retinoblastoma. After RNA extraction and synthesis of cDNA, multiplex PCR was done to evaluate the presence of rotavirus, norovirus, astrovirus, and enterovirus.
RESULTS
There were 9 (6.9%), 7 (5.4%), 3 (2.3%), and 6 (4.6%) cases of rotavirus, norovirus, astrovirus, and enterovirus detected, respectively. One case of co-infection with astrovirus and norovirus was observed.
CONCLUSIONS
This is the first report from Iran which identified the presence of common RNA viruses causing diarrhoea in immunocompromised children. Increased awareness of these viruses will enable healthcare professionals to improve strategies and policies to control spread and infection caused by these viruses.
PubMed: 38855735
DOI: 10.1016/j.infpip.2024.100370 -
Translational Andrology and Urology May 2024Small cell neuroendocrine prostate cancer (SCNC) is a rare aggressive type of neuroendocrine prostate cancer (NEPC) characterized by aggressive clinical course and lack...
BACKGROUND
Small cell neuroendocrine prostate cancer (SCNC) is a rare aggressive type of neuroendocrine prostate cancer (NEPC) characterized by aggressive clinical course and lack of response to hormone therapy.
CASE DESCRIPTION
We present a case report of a 60-year-old man diagnosed with a histologically confirmed primary metastatic (bone, lymph nodes and visceral) SCNC with small components of an adenocarcinoma with clinical symptoms mimicking an acute prostatitis. Of note, serum based neuroendocrine markers (carcinoembryonic antigen, chromogranin A) were negative and the patient had a prostate-specific antigen (PSA) elevation. Genetic testing of tumor tissue revealed breast cancer gene 2 () copy number loss and a retinoblastoma gene () mutation reflecting again the aggressiveness of the disease. Germline testing for the copy number loss was unremarkable. After 6 cycles of carboplatin and etoposide in combination with androgen deprivation therapy (ADT) the Eastern Cooperative Oncology Group (ECOG) performance status has improved from 3 to 0, in addition the patient was free of pain. In line with clinical improvement, both prostate-specific membrane antigen (PSMA) and fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) revealed a significant reduction of metastatic load. Currently, the patient is treated with ADT plus apalutamide.
CONCLUSIONS
We demonstrate for the first time a case of a primary metastatic SCNC with adenocarcinoma components successfully treated by the combination of platinum-based chemotherapy plus hormonal therapy. In addition, we provide a literature overview on management of SCNC as there is no standard treatment established for this disease.
PubMed: 38855597
DOI: 10.21037/tau-23-541 -
Translational Lung Cancer Research May 2024Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have shown significant activity against several solid tumors by reducing the phosphorylation of the canonical CDK4/6...
CDK4/6 inhibitor abemaciclib combined with low-dose radiotherapy enhances the anti-tumor immune response to PD-1 blockade by inflaming the tumor microenvironment in Rb-deficient small cell lung cancer.
BACKGROUND
Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have shown significant activity against several solid tumors by reducing the phosphorylation of the canonical CDK4/6 substrate retinoblastoma (Rb) protein, while the anti-tumor effect of CDK4/6 inhibitors on Rb-deficient tumors is not clear. Most small cell lung cancers (SCLCs) are Rb-deficient and show very modest response to immune checkpoint blockade (ICB) despite recent advances in the use of immunotherapy. Here, we aimed to investigate the direct effect of CDK4/6 inhibition on SCLC cells and determine its efficacy in combination therapy for SCLC.
METHODS
The immediate impact of CDK4/6 inhibitor abemaciclib on cell cycle, cell viability and apoptosis in four SCLC cell lines was initially checked. To explore the effect of abemaciclib on double-strand DNA (ds-DNA) damage induction and the combination impact of abemaciclib coupled with radiotherapy (RT), western blot, immunofluorescence (IF) and quantitative real-time polymerase chain reaction (qRT-PCR) were performed. An Rb-deficient immunocompetent murine SCLC model was established to evaluate efficacy of abemaciclib in combination therapy. Histological staining, flow cytometry analysis and RNA sequencing were performed to analyze alteration of infiltrating immune cells in tumor microenvironment (TME).
RESULTS
Here, we demonstrated that abemaciclib induced increased ds-DNA damage in Rb-deficient SCLC cells. Combination of abemaciclib and RT induced more cytosolic ds-DNA, and activated the STING pathway synergistically. We further showed that combining low doses of abemaciclib with low-dose RT (LDRT) plus anti-programmed cell death protein-1 (anti-PD-1) antibody substantially potentiated CD8 T cell infiltration and significantly inhibited tumor growth and prolonged survival in an Rb-deficient immunocompetent murine SCLC model.
CONCLUSIONS
Our results define previously uncertain DNA damage-inducing properties of CDK4/6 inhibitor abemaciclib in Rb-deficient SCLCs, and demonstrate that low doses of abemaciclib combined with LDRT inflame the TME and enhance the efficacy of anti-PD-1 immunotherapy in SCLC model, which represents a potential novel therapeutic strategy for SCLC.
PubMed: 38854937
DOI: 10.21037/tlcr-24-33